Central nervous system (CNS) cancer

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37 regimens on this page
58 variants on this page

Contents


Guidelines

ASCO

ESMO

NCCN

Anaplastic glioma - adjuvant therapy

PCV

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PCV: Procarbazine, CCNU, Vincristine

Regimen

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III Radiation therapy Seems not superior
Temozolomide Seems not superior

Chemotherapy

8-week cycle for 4 cycles

Patients with stable disease or better received 2 more cycles of PCV. At time of disease progression patients proceeded to receive radiation therapy.

References

  1. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed

Radiation therapy

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Regimen

Study Evidence Comparator Efficacy
MRC Brain Tumor Working Party 2001 Phase III RT -> PCV Seems not superior
van den Bent et al. 2006 (EORTC 26951) Phase III RT -> PCV Inferior PFS
Wick et al. 2009 (NOA-04) Phase III PCV Seems not superior
Temozolomide Seems not superior

Adjuvant radiation alone; used as a comparator arm in the referenced trials.

Radiotherapy

  • Radiation therapy with 1.8 to 2 Gy fractions given over 6 weeks for a total dose of 60 Gy

Patients on the NOA-04 trial were randomized to PCV versus temozolomide at the time of progression.

References

  1. Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001 Jan 15;19(2):509-18. link to original article contains verified protocol PubMed
  2. van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006 Jun 20;24(18):2715-22. link to original article contains verified protocol PubMed
    1. Update: van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013 Jan 20;31(3):344-50. Epub 2012 Oct 15. link to original article PubMed
  3. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed

RT -> Carmustine

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Regimen

Study Evidence Comparator Efficacy
Shapiro et al. 1989 (BTCG 8001) Phase III Carmustine/Procarbazine & RT Seems not superior
Carmustine & Hydrea/Procarbazine & VM-26 & RT Seems not superior

Radiotherapy

  • Radiation therapy starting within 3 weeks after surgical resection, with ONE of the following:
    • Whole brain: 172 cGy (rads) fractions x 35 fractions, given over 7 weeks for a total dose of 6020 cGy (6020 rads/~1700 rets)
    • Whole brain & cone down: 172 cGy (rads) fractions x 25 fractions, given over 5 weeks for a total dose of 4300 cGy (4300 rads), then coned-down boost of 172 cGy (rads) fractions x 10 fractions, given over 2 weeks for a dose of 1720 cGy (rads), and a total cumulative dose of 6020 cGy (rads)

One course, followed by:

Chemotherapy

Supportive care

  • Pulmonary function tests (PFTs) checked before start of therapy, and then when cumulative dose of Carmustine (BiCNU) reaches 800 mg/m2 and 1200 mg/m2

8-week cycles, with no more than a maximum cumulative dose of 1500 mg/m2 Carmustine (BiCNU) given

References

  1. Shapiro WR, Green SB, Burger PC, Mahaley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA et al. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989 Jul;71(1):1-9. link to original article contains verified protocol PubMed

RT -> PCV

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RT -> PCV: Radiation Therapy followed by Procarbazine, CCNU (Lomustine), Vincristine

Regimen #1

Study Evidence Comparator Efficacy
MRC Brain Tumor Working Party 2001 Phase III Radiation therapy Seems not superior

Radiation therapy starts preferably within 3, but no more than 6, weeks after neurosurgery:

Radiotherapy

  • Either:
    • 2.25 Gy fractions x 20 fractions, given 5 days per week over 4 weeks, total dose of 45 Gy
    • or 2 Gy fractions x 30 fractions, given 5 days per week over 6 weeks, total dose of 60 Gy

Chemotherapy begins 3 to 4 weeks after completion of radiation therapy:

Chemotherapy

Supportive medications

  • Corticosteroid use was left up to physician discretion. It was recommended to not discontinue steroids until at least 6 weeks after radiation therapy. If it was to be discontinued, it should be tapered down gradually over several weeks, or could be titrated down to the lowest tolerated dose.

6-week cycle for up to 12 cycles

Regimen #2

Study Evidence Comparator Efficacy
van den Bent et al. 2006 (EORTC 26951) Phase III Radiation therapy Superior PFS

van den Bent et al. 2013 noted that 1p/19q-codeleted tumors received the more benefit from adjuvant PCV as compared to tumors without 1p/19q codeletion.

Radiation therapy starts within 6 weeks after surgery.

Radiotherapy

  • Radiation therapy, 1.8 Gy fractions x 25 fractions, given 5 days per week, total dose of 45 Gy to the planning target volume (PTV-1); then a boost of 1.8 Gy fractions x 8 fractions, given 5 days per week, total boost dose of 14.4 Gy to the PTV-2, for a total cumulative dose of 59.4 Gy

Chemotherapy begins within 4 weeks after completion of radiation therapy:

Chemotherapy

Supportive medications

6-week cycle for 6 cycles

References

  1. Levin VA, Silver P, Hannigan J, Wara WM, Gutin PH, Davis RL, Wilson CB. Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys. 1990 Feb;18(2):321-4. PubMed
  2. Medical Research Council Brain Tumor Working Party. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a Medical Research Council trial. J Clin Oncol. 2001 Jan 15;19(2):509-18. link to original article contains verified protocol PubMed
  3. van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006 Jun 20;24(18):2715-22. link to original article contains verified protocol PubMed
    1. Update: van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Enting RH, French PJ, Dinjens WN, Vecht CJ, Allgeier A, Lacombe D, Gorlia T, Hoang-Xuan K. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013 Jan 20;31(3):344-50. Epub 2012 Oct 15. link to original article PubMed
  4. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society.. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012 Jul;13(7):707-15. link to original article contains protocol PubMed

Temozolomide (Temodar)

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Regimen #1, dose-dense

Study Evidence Comparator Efficacy
Wick et al. 2012 (NOA-08) Phase III Radiation therapy Seems to have non-inferior OS

Chemotherapy

14-day cycles

Regimen #2

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III PCV Seems not superior
Radiation therapy Seems not superior

Chemotherapy

28-day cycle for 8 cycles

Patients with stable disease or better received 4 more cycles of temozolomide. At time of disease progression patients proceeded to receive radiation therapy.

Regimen #3

Study Evidence
Mikkelsen et al. 2009 Non-randomized

This regimen is meant for patients with 1p/19q loss of heterozygosity (LOH).

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycles 1 & 2: 150 mg/m2 PO once per day on days 1 to 5, on empty stomach
    • Cycle 3 onwards (if no myelosuppression): 200 mg/m2 PO once per day on days 1 to 5, on empty stomach

28-day cycles

Regimen #4

Study Evidence
Taliansky-Aronov et al. 2006 Non-randomized

Chemotherapy

Supportive medications

  • Corticosteroids could be continued at same dose or reduced, but not increased while on study

28-day cycles, given until progression of disease or, in patients with stable disease, up to 24 months

References

  1. Taliansky-Aronov A, Bokstein F, Lavon I, Siegal T. Temozolomide treatment for newly diagnosed anaplastic oligodendrogliomas: a clinical efficacy trial. J Neurooncol. 2006 Sep;79(2):153-7. Epub 2006 Jul 20. link to original article contains verified protocol PubMed
  2. Mikkelsen T, Doyle T, Anderson J, Margolis J, Paleologos N, Gutierrez J, Croteau D, Hasselbach L, Avedissian R, Schultz L. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009 Mar;92(1):57-63. Epub 2008 Nov 15. link to original article contains verified protocol PubMed content property of HemOnc.org
  3. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed
  4. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society.. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012 Jul;13(7):707-15. link to original article contains protocol PubMed

Temozolomide -> Temozolomide & RT -> Temozolomide

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Regimen

Study Evidence
Mikkelsen et al. 2009 Non-randomized

This regimen is meant for patients without 1p/19q loss of heterozygosity (LOH).

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycles 1 & 2: 150 mg/m2 PO once per day on days 1 to 5, on empty stomach
    • Cycle 3 onwards (if no myelosuppression): 200 mg/m2 PO once per day on days 1 to 5, on empty stomach

28-day cycle for 2 to 4 cycles, followed by:

Chemoradiotherapy

  • Temozolomide (Temodar) 75 mg/m2 PO once per day during radiation therapy
  • Concurrent radiation therapy with a total dose of 60 Gy

One course, followed by:

Chemotherapy

28-day cycles

References

  1. Mikkelsen T, Doyle T, Anderson J, Margolis J, Paleologos N, Gutierrez J, Croteau D, Hasselbach L, Avedissian R, Schultz L. Temozolomide single-agent chemotherapy for newly diagnosed anaplastic oligodendroglioma. J Neurooncol. 2009 Mar;92(1):57-63. Epub 2008 Nov 15. link to original article contains verified protocol PubMed content property of HemOnc.org

Anaplastic glioma - recurrent disease, salvage therapy

Bevacizumab (Avastin)

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Regimen

Study Evidence
Chamberlain et al. 2008 Non-randomized

Chemotherapy

Supportive medications

  • Use of steroids allowed for control of neurologic signs and symptoms

14-day cycles

References

  1. Chamberlain MC, Johnston S. Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. J Neurooncol. 2009 Feb;91(3):359-67. Epub 2008 Oct 25. J Neurooncol. 2009 Feb;91(3):359-67. Epub 2008 Oct 25. link to original article contains verified protocol PubMed
  2. Retrospective: Chamberlain MC, Johnston S. Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer. 2009 Apr 15;115(8):1734-43. link to original article PubMed

Bevacizumab & Carboplatin

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Regimen #1

Study Evidence
Thompson et al. 2010 Retrospective

Chemotherapy

28-day cycles

Regimen #2

Study Evidence
Norden et al. 2008 Retrospective

Chemotherapy

References

  1. Retrospective: Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article PubMed
  2. Retrospective: Thompson EM, Dosa E, Kraemer DF, Neuwelt EA. Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery. 2010 Jul;67(1):87-93. link to original article PubMed

Bevacizumab & Irinotecan

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Regimen

Study Evidence
Vredenburgh et al. 2007 Phase II

Note: Vredenburgh et al. 2007 described 6-week cycles in which treatment was every 2 weeks and was otherwise identical, so its entry was consolidated with Taillibert et al. 2009.

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once on day 1, given first
    • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 340 mg/m2 IV over 90 minutes once on day 1, given first
  • Bevacizumab (Avastin) 10 mg/kg IV once on day 1, given second
    • Infusion times for bevacizumab are 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later

Supportive medications

  • "Appropriate antiemetics"

14-day cycles

References

  1. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007 Feb 15;13(4):1253-9. link to original article contains verified protocol PubMed
  2. Retrospective: Taillibert S, Vincent LA, Granger B, Marie Y, Carpentier C, Guillevin R, Bellanger A, Mokhtari K, Rousseau A, Psimaras D, Dehais C, Sierra del Rio M, Meng Y, Laigle-Donadey F, Hoang-Xuan K, Sanson M, Delattre JY. Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Neurology. 2009 May 5;72(18):1601-6. link to original article PubMed

Cyclophosphamide (Cytoxan)

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Regimen

Study Evidence
Chamberlain et al. 2006 Phase II

Chemotherapy

Supportive medications

28-day cycles

References

  1. Chamberlain MC, Tsao-Wei DD, Groshen S. Salvage chemotherapy with cyclophosphamide for recurrent temozolomide-refractory anaplastic astrocytoma. Cancer. 2006 Jan 1;106(1):172-9. link to original article contains verified protocol PubMed

Etoposide (Vepesid)

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Regimen

Study Evidence
Fulton et al. 1996 Phase II

Chemotherapy

Given until progression of disease or unacceptable toxicity

References

  1. Fulton D, Urtasun R, Forsyth P. Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol. 1996 Feb;27(2):149-55. link to original article contains verified protocol PubMed

Irinotecan (Camptosar)

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Regimen #1

Study Evidence
Chamberlain et al. 2008 Phase II

Chemotherapy

  • Irinotecan (Camptosar) 350 mg/m2 IV over 120 minutes once on day 1
    • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 600 mg/m2 IV over 120 minutes once on day 1

Supportive medications

21-day cycles

Regimen #2

Study Evidence
Friedman et al. 1999 Phase II

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 1, 8, 15, 22
    • If tolerated, dose could be increased to 150 mg/m2 IV once per day on days 1, 8, 15, 22

Supportive medications

  • Steroids at lowest dose necessary
  • Avoid laxatives and magnesium-containing antacids due to potential for diarrhea

42-day (6-week) cycles, given until progression of disease or unacceptable toxicity

References

  1. Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, Parry M, Houghton PJ, Lovell S, Rasheed K, Cloughsey T, Stewart ES, Colvin OM, Provenzale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, Elfring GL, Miller LL. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol. 1999 May;17(5):1516-25. link to original article contains verified protocol PubMed
  2. Phase I: Chamberlain MC. Salvage chemotherapy with CPT-11 for recurrent oligodendrogliomas. J Neurooncol. 2002 Sep;59(2):157-63. link to original article PubMed
  3. Chamberlain MC, Wei-Tsao DD, Blumenthal DT, Glantz MJ. Salvage chemotherapy with CPT-11 for recurrent temozolomide-refractory anaplastic astrocytoma. Cancer. 2008 May 1;112(9):2038-45. link to original article contains verified protocol PubMed

Lomustine (Ceenu)

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  • Note: The NCCN, Central Nervous System Cancers version 1.2013 lists this regimen (Wick et al. 2010) with Lomustine (Ceenu) salvage therapy in glioblastoma multiforme as an option for treatment of anaplastic gliomas. This study only included patients who had histologically confirmed WHO grade 4 glioblastoma. The NCCN also listed the following phase II trial as a reference for use of Carmustine (BiCNU)/Lomustine (Ceenu) in recurrent malignant glioma, but the nitrosourea used was fotemustine (FTM): R. Soffietti, R. Rudà, E. Trevisan, E. Picco, D. Guarneri, M. Caroli, M. Fabrini, V. Scotti. Phase II study of bevacizumab and nitrosourea in patients with recurrent malignant glioma: A multicenter Italian study. CNS Tumors 2012 J Clin Oncol 27:15s, 2009 (suppl; abstr 2012). 2009 ASCO Annual Meeting abstract 2012. link to abstract

PCV

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PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen #1

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III Temozolomide Seems not superior

All patients had progressed after previously receiving radiation therapy, salvage temozolomide, or salvage radiation therapy.

Chemotherapy

8-week cycles until progression

At progression, patients who had not previously received temozolomide proceeded to receive salvage temozolomide.

Regimen #2

Study Evidence
Levin et al. 1980 Non-randomized

Chemotherapy

6-week cycles, given until progression of disease or unacceptable toxicity

Regimen #3, higher doses

Study Evidence
Cairncross et al. 1994 Phase II

Chemotherapy

6-week cycles, given until progression of disease or unacceptable toxicity

References

  1. Levin VA, Edwards MS, Wright DC, Seager ML, Schimberg TP, Townsend JJ, Wilson CB. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980 Feb-Mar;64(2-3):237-44. contains protocol PubMed
  2. Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J, Fulton D, Dropcho E, Stewart D, Schold C Jr et al. Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994 Oct;12(10):2013-21. link to original article contains verified protocol PubMed
  3. Kappelle AC, Postma TJ, Taphoorn MJ, Groeneveld GJ, van den Bent MJ, van Groeningen CJ, Zonnenberg BA, Sneeuw KC, Heimans JJ. PCV chemotherapy for recurrent glioblastoma multiforme. Neurology. 2001 Jan 9;56(1):118-20. link to original article PubMed
  4. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed

Radiation therapy

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Regimen

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III PCV Seems not superior
Temozolomide Seems not superior

Patients had previously received PCV versus temozolomide prior to progression.

Radiotherapy

  • Radiation therapy with 1.8 to 2 Gy fractions given over 6 weeks for a total dose of 60 Gy

Patients in NOA-04 who progressed then received PCV if they had previously received temozolomide, or temozolomide if they had previously received PCV.

References

  1. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed

Temozolomide (Temodar)

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Regimen #1

Study Evidence Comparator Efficacy
Wick et al. 2009 (NOA-04) Phase III PCV Seems not superior

All patients had progressed after previously receiving radiation therapy, salvage PCV, or salvage radiation therapy.

Chemotherapy

28-day cycles until progression

At progression, patients who had not previously received PCV proceeded to receive salvage PCV.

Regimen #2, continuous therapy

Study Evidence
Perry et al. 2008 (RESCUE) Phase II

Patients who undergo conventional temozolomide therapy, have surgery and radiation therapy, and then relapse receive:

Chemotherapy

28-day cycles

Patients with progressive disease are changed to:

Given until progression of disease or unacceptable toxicity

Regimen #3, traditional dosing

Study Evidence
Nicholson et al. 2007 Non-randomized

Chemotherapy

  • Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
    • Patients who previously received craniospinal irradiation (CSI) instead received 180 mg/m2 PO once per day on days 1 to 5

28-day cycle for up to 11 cycles

Regimen #4

Study Evidence
Yung et al. 1999 Phase II

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Patients who had never previously received chemotherapy: 200 mg/m2 PO once per day on days 1 to 5
    • Patients who previously received chemotherapy started with 150 mg/m2 PO once per day on days 1 to 5, which could be increased as tolerated to 200 mg/m2 PO once per day on days 1 to 5

Supportive medications

28-day cycle for up to 2 years

References

  1. Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O'Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999 Sep;17(9):2762-71. link to original article contains verified protocol PubMed
  2. Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, Friedman H, Harris MB, Tedeschi-Blok N, Mazewski C, Sato J, Reaman GH. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group. Cancer. 2007 Oct 1;110(7):1542-50. link to original article contains verified protocol PubMed
  3. Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach. Cancer. 2008 Oct 15;113(8):2152-7. link to original article contains verified protocol PubMed
    1. Update: Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr 20;28(12):2051-7. Epub 2010 Mar 22. link to original article contains verified protocol PubMed
  4. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009 Dec 10;27(35):5874-80. Epub 2009 Nov 9. link to original article contains verified protocol PubMed

Glioblastoma multiforme chemoradiation & adjuvant therapy

Carmustine & RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Shapiro et al. 1989 (BTCG 8001) Phase III Carmustine/Procarbazine & RT Seems not superior
Carmustine & Hydrea/Procarbazine & VM-26 & RT Seems not superior

Radiotherapy

  • Radiation therapy starting within 3 weeks after surgical resection, with ONE of the following:
    • Whole brain: 172 cGy (rads) fractions x 35 fractions, given over 7 weeks for a total dose of 6020 cGy (6020 rads/~1700 rets)
    • Whole brain & cone down: 172 cGy (rads) fractions x 25 fractions, given over 5 weeks for a total dose of 4300 cGy (4300 rads), then coned-down boost of 172 cGy (rads) fractions x 10 fractions, given over 2 weeks for a dose of 1720 cGy (rads), and a total cumulative dose of 6020 cGy (rads)

One course, followed by:

Chemotherapy

Supportive care

  • Pulmonary function tests (PFTs) checked before start of therapy, and then when cumulative dose of Carmustine (BiCNU) reaches 800 mg/m2 and 1200 mg/m2

8-week cycles, with no more than a maximum cumulative dose of 1500 mg/m2 Carmustine (BiCNU) given

References

  1. Shapiro WR, Green SB, Burger PC, Mahaley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA et al. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989 Jul;71(1):1-9. link to original article contains verified protocol PubMed

Radiation therapy

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Regimen #1, standard radiotherapy

Study Evidence Comparator Efficacy
Stupp et al. 2005 Phase III Temozolomide & RT -> Temozolomide Inferior OS
Malmström et al. 2012 (NCBTSG) Phase III Hypofractionated radiotherapy Not reported
Temozolomide Inferior OS

Adjuvant radiotherapy alone; used as a comparator arm in the referenced trials.

Regimen #2, hypofractionated radiotherapy

Study Evidence Comparator Efficacy
Malmström et al. 2012 (NCBTSG) Phase III Standard radiotherapy Not reported
Temozolomide Seems not superior

Adjuvant radiotherapy alone; used as a comparator arm in the referenced trials.

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article contains verified protocol PubMed
  2. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012 Sep;13(9):916-26. link to original article PubMed

Temozolomide (Temodar)

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Regimen

Study Evidence Comparator Efficacy
Malmström et al. 2012 (NCBTSG) Phase III Hypofractionated radiotherapy Seems not superior
Standard radiotherapy Superior OS

|}

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. Malmström A, Grønberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R; Nordic Clinical Brain Tumour Study Group (NCBTSG).. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012 Sep;13(9):916-26. link to original article contains verified protocol PubMed

Temozolomide & RT -> Temozolomide

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Stupp et al. 2005 Phase III Radiotherapy Superior OS
Gilbert et al. 2014 Phase III Bevacizumab, Temozolomide, RT Inferior PFS
Chinot et al. 2014 Phase III Bevacizumab, Temozolomide, RT Inferior PFS

Note: although this regimen had inferior PFS in Gilbert et al. 2014, the effect size did not reach the prespecified improvement target.

Chemoradiotherapy

  • Temozolomide (Temodar) 75 mg/m2 PO once per day, used starting the first day of radiation therapy until the last day of radiation therapy, and no longer than 49 days
  • Concurrent radiation therapy, 2 Gy fractions x 30 fractions given 5 days per week, for a total dose of 60 Gy

Supportive medications

One course

4 weeks after completion of radiation therapy, patients received additional therapy:

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Cycle 1: 150 mg/m2 PO once per day on days 1 to 5
    • If tolerated, in cycles 2 to 6: 200 mg/m2 PO once per day on days 1 to 5

Supportive medications

28-day cycle for 6 cycles

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005 Mar 10;352(10):997-1003. link to original article PubMed
  2. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. link to original article PubMed
  3. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. link to original article PubMed

Glioblastoma multiforme - recurrent disease, salvage therapy

Bevacizumab (Avastin)

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Regimen #1

Study Evidence
Friedman et al. 2009 Phase II

Chemotherapy

6-week cycle for up to 104 weeks, until progression of disease, or unacceptable toxicity

Regimen #2

Study Evidence
Kreisl et al. 2008 Phase II

Chemotherapy

4-week cycles, given until progression of disease, or unacceptable toxicity; upon progression, patients received Irinotecan (Camptosar) & Bevacizumab (Avastin)

References

  1. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009 Feb 10;27(5):740-5. Epub 2008 Dec 29. link to original article contains verified protocol PubMed
  2. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. Epub 2009 Aug 31. link to original article contains verified protocol PubMed

Bevacizumab & Carboplatin

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Regimen #1

Study Evidence
Thompson et al. 2010 Retrospective

Chemotherapy

28-day cycles

Regimen #2

Study Evidence
Norden et al. 2008 Retrospective

Chemotherapy

References

  1. Retrospective: Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article PubMed
  2. Retrospective: Thompson EM, Dosa E, Kraemer DF, Neuwelt EA. Treatment with bevacizumab plus carboplatin for recurrent malignant glioma. Neurosurgery. 2010 Jul;67(1):87-93. link to original article PubMed

Bevacizumab & Irinotecan

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Regimen #1, every 2 week schedule

Study Evidence
Chen et al. 2007 Pilot, >20 pts
Vredenburgh et al. 2007 Phase II
Norden et al. 2008 Phase II
Friedman et al. 2009 Phase II

Note: Friedman et al. 2009 described 6-week cycles in which treatment was every 2 weeks, given up to 104 weeks, and was otherwise identical, so its entry was consolidated with the other ones here.

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once on day 1, given first
    • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 340 mg/m2 (Vredenburgh et al. 2007 & Norden et al. 2008) or 350 mg/m2 (Chen et al. 2007) IV over 90 minutes once on day 1, given first
  • Bevacizumab (Avastin) 10 mg/kg IV once on day 1, given second, 90 minutes after the start of irinotecan
    • Infusion times for bevacizumab are 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later

Supportive medications

  • Steroids were generally maintained at the same dose

14-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2

Study Evidence
Vredenburgh et al. 2007 Phase II, <20 pts

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 22, 29, given first
    • Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) are treated with a higher dose: 350 mg/m2 IV over 90 minutes once per day on days 1, 8, 22, 29, given first
  • Bevacizumab (Avastin) 15 mg/kg IV once per day on days 1 & 22, given second, 90 minutes after the start of irinotecan
    • Infusion times for bevacizumab are 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later

Supportive medications

  • Steroids were generally maintained at the same dose

42-day (6-week) cycles, given until progression of disease or unacceptable toxicity

References

  1. Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, Satyamurthy N, Pope W, Lai A, Phelps ME, Cloughesy T. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007 Oct 20;25(30):4714-21. link to original article contains verified protocol PubMed
  2. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007 Oct 20;25(30):4722-9. link to original article contains verified protocol PubMed
  3. Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008 Mar 4;70(10):779-87. link to original article contains verified protocol PubMed
  4. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. Epub 2009 Aug 31. link to original article contains verified protocol PubMed

Carmustine (BiCNU)

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Regimen

Study Evidence
Brandes et al. 2004 Phase II

Chemotherapy

Supportive medications

8-week cycle for up to 6 cycles

References

  1. Brandes AA, Tosoni A, Amistà P, Nicolardi L, Grosso D, Berti F, Ermani M. How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology. 2004 Oct 12;63(7):1281-4. link to original article contains verified protocol PubMed

Cyclophosphamide (Cytoxan)

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Regimen

Study Evidence
Chamberlain & Tsao-Wei, 2004 Phase II

Chemotherapy

Supportive medications

28-day cycles

References

  1. Chamberlain MC, Tsao-Wei DD. Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer. 2004 Mar 15;100(6):1213-20. link to original article contains verified protocol PubMed

Hydroxyurea & Imatinib

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Regimen

Study Evidence
Dresemann et al. 2005 Non-randomized

Chemotherapy

Given until progression of disease

References

  1. Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol. 2005 Oct;16(10):1702-8. Epub 2005 Jul 20. link to original article contains verified protocol PubMed

Irinotecan (Camptosar)

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Regimen

Study Evidence
Friedman et al. 1999 Phase II

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV once per day on days 1, 8, 15, 22
    • If tolerated, dose could be increased to 150 mg/m2 IV once per day on days 1, 8, 15, 22

Supportive medications

  • Steroids at lowest dose necessary
  • Avoid laxatives and magnesium-containing antacids due to potential for diarrhea

42-day (6-week) cycles, given until progression of disease or unacceptable toxicity

References

  1. Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, Parry M, Houghton PJ, Lovell S, Rasheed K, Cloughsey T, Stewart ES, Colvin OM, Provenzale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, Elfring GL, Miller LL. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol. 1999 May;17(5):1516-25. link to original article contains verified protocol PubMed

Lomustine (Ceenu)

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Regimen

Study Evidence Comparator Efficacy
Wick et al. 2010 Phase III Enzastaurin Seems not superior

Chemotherapy

Supportive medications

  • Enzyme-inducing antiepileptic drugs (EIAEDs) needed to be discontinued 14 days before enrolling in the trial

6-week cycles, given until progression of disease or unacceptable toxicity

References

  1. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. link to original article contains verified protocol PubMed

PCV

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PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen #1

Study Evidence
Levin et al. 1980 Non-randomized

Chemotherapy

6-week cycles, given until progression of disease or unacceptable toxicity

Regimen #2, higher doses

Study Evidence
Cairncross et al. 1994 Phase II

Chemotherapy

6-week cycles, given until progression of disease or unacceptable toxicity

References

  1. Levin VA, Edwards MS, Wright DC, Seager ML, Schimberg TP, Townsend JJ, Wilson CB. Modified procarbazine, CCNU, and vincristine (PCV 3) combination chemotherapy in the treatment of malignant brain tumors. Cancer Treat Rep. 1980 Feb-Mar;64(2-3):237-44. contains protocol PubMed
  2. Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, Buckner J, Fulton D, Dropcho E, Stewart D, Schold C Jr et al. Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994 Oct;12(10):2013-21. link to original article contains verified protocol PubMed

Procarbazine (Matulane)

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Regimen

Study Evidence
Yung et al. 2000 Phase II

Chemotherapy

  • Procarbazine (Matulane) as follows:
    • Patients who had never previously received chemotherapy: 150 mg/m2 PO once per day on days 1 to 28
    • Patients who previously received chemotherapy started with 125 mg/m2 PO once per day on days 1 to 28

Supportive medications

8-week cycle for up to 2 years, progression of disease, or unacceptable toxicity

References

  1. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588-93. link to original article contains verified protocol PubMed

Temozolomide (Temodar)

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Regimen #1, continuous therapy

Study Evidence
Perry et al. 2008 (RESCUE) Phase II

Chemotherapy

Patients who have first recurrence after surgery and conventional external beam radiation:

28-day cycles

Patients with progressive disease are changed to:

Given until progression of disease or unacceptable toxicity

Patients who had recurrent/progressive disease after surgery and concurrent radiation and temozolomide are treated with:

Given until progression of disease or unacceptable toxicity

Regimen #2, traditional dosing

Study Evidence
Nicholson et al. 2007 Non-randomized

Chemotherapy

  • Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
    • Patients who previously received craniospinal irradiation (CSI) instead received 180 mg/m2 PO once per day on days 1 to 5

28-day cycle for up to 11 cycles

Regimen #3

Study Evidence
Yung et al. 2000 Phase II

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Patients who had never previously received chemotherapy: 200 mg/m2 PO once per day on days 1 to 5
    • Patients who previously received chemotherapy started with 150 mg/m2 PO once per day on days 1 to 5

28-day cycle for up to 2 years, until progression of disease, or unacceptable toxicity

References

  1. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000 Sep;83(5):588-93. link to original article contains verified protocol PubMed
  2. Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, Friedman H, Harris MB, Tedeschi-Blok N, Mazewski C, Sato J, Reaman GH. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group. Cancer. 2007 Oct 1;110(7):1542-50. link to original article contains verified protocol PubMed
  3. Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the "rescue" approach. Cancer. 2008 Oct 15;113(8):2152-7. link to original article contains verified protocol PubMed
    1. Update: Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot JF. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr 20;28(12):2051-7. Epub 2010 Mar 22. link to original article contains verified protocol PubMed

Supratentorial astrocytoma or oligodendroglioma chemoradiation & adjuvant therapy

Radiation therapy

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Regimen

Study Evidence Comparator Efficacy
Shaw et al. 2012 (RTOG 9802) Phase III RT -> PCV Inferior PFS
Baumert et al. 2016 (EORTC 22033-26033) Phase III Temozolomide Seems not superior

Used as a comparator arm; see references for details.

References

  1. Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta MP. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012 Sep 1;30(25):3065-70. link to original article link to PMC article contains verified protocol PubMed
  2. Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K, Brandes AA, Kantor G, Taphoorn MJ, Hassel MB, Hartmann C, Ryan G, Capper D, Kros JM, Kurscheid S, Wick W, Enting R, Reni M, Thiessen B, Dhermain F, Bromberg JE, Feuvret L, Reijneveld JC, Chinot O, Gijtenbeek JM, Rossiter JP, Dif N, Balana C, Bravo-Marques J, Clement PM, Marosi C, Tzuk-Shina T, Nordal RA, Rees J, Lacombe D, Mason WP, Stupp R. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1521-1532. link to original article contains protocol PubMed

RT -> PCV

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RT -> PCV: Radiation Therapy followed by Procarbazine, CCNU (Lomustine), Vincristine

Regimen

Study Evidence Comparator Efficacy
Shaw et al. 2012 (RTOG 9802) Phase III Radiotherapy Superior PFS

Radiotherapy

  • Radiation therapy with 1.8 Gy fractions given in 30 fractions over 6 weeks, for a total dose of 54 Gy

One course, followed by:

Chemotherapy

8-week cycle for 6 cycles

References

  1. Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta MP. Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol. 2012 Sep 1;30(25):3065-70. link to original article link to PMC article contains verified protocol PubMed

Temozolomide (Temodar)

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Regimen

Study Evidence Comparator Efficacy
Baumert et al. 2016 (EORTC 22033-26033) Phase III Radiotherapy Seems not superior

Chemotherapy

28-day cycle for up to 12 cycles

References

  1. Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K, Brandes AA, Kantor G, Taphoorn MJ, Hassel MB, Hartmann C, Ryan G, Capper D, Kros JM, Kurscheid S, Wick W, Enting R, Reni M, Thiessen B, Dhermain F, Bromberg JE, Feuvret L, Reijneveld JC, Chinot O, Gijtenbeek JM, Rossiter JP, Dif N, Balana C, Bravo-Marques J, Clement PM, Marosi C, Tzuk-Shina T, Nordal RA, Rees J, Lacombe D, Mason WP, Stupp R. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016 Nov;17(11):1521-1532. link to original article contains protocol PubMed

Supratentorial astrocytoma or oligodendroglioma - recurrent or progressive, low-grade disease

Carboplatin (Paraplatin)

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Regimen

Study Evidence
Moghrabi et al. 1998 Phase II

Chemotherapy

Supportive medications

  • Hydration for 1 hour before chemotherapy, and for 1 hour after chemotherapy; total volume including carboplatin is 900 mL/m2

28-day cycle for up to 12 cycles beyond the maximum response, given until progression of disease, or unacceptable toxicity

References

  1. Moghrabi A, Friedman HS, Ashley DM, Bottom KS, Kerby T, Stewart E, Bruggers C, Provenzale JM, Champagne M, Hershon L, Watral M, Ryan J, Rasheed K, Lovell S, Korones D, Fuchs H, George T, McLendon RE, Friedman AH, Buckley E, Longee DC. Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas. Neurosurg Focus. 1998 Apr 15;4(4):e3. link to original article contains verified protocol PubMed

Carboplatin & Teniposide

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Regimen

Study Evidence
Brandes et al. 2003 Phase II

Chemotherapy

Supportive medications

  • Prophylactic 5-HT3 antagonists routinely used
  • Lowest dose of corticosteroids necessary to maintain neurologic stability
  • Antiepileptic medications for all patients

28-day cycle for up to 10 cycles

References

  1. Brandes AA, Basso U, Vastola F, Tosoni A, Pasetto LM, Jirillo A, Lonardi S, Paris MK, Koussis H, Monfardini S, Ermani M. Carboplatin and teniposide as third-line chemotherapy in patients with recurrent oligodendroglioma or oligoastrocytoma: a phase II study. Ann Oncol. 2003 Dec;14(12):1727-31. link to original article contains verified protocol PubMed

Cisplatin & Etoposide

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Regimen

Study Evidence
Massimino et al. 2010 Non-randomized

Note: In children <1 year old or <10 kg, "doses were adjusted to their weight"--reference does not say exactly how doses are adjusted.

Chemotherapy

Supportive medications

  • Hydration for 2 hours before chemotherapy, and for 2 hours after chemotherapy

28-day cycle for 4 cycles, then 35-day cycle for 3 cycles, then 42-day cycle for 3 cycles

References

  1. Massimino M, Spreafico F, Riva D, Biassoni V, Poggi G, Solero C, Gandola L, Genitori L, Modena P, Simonetti F, Potepan P, Casanova M, Meazza C, Clerici CA, Catania S, Sardi I, Giangaspero F. A lower-dose, lower-toxicity cisplatin-etoposide regimen for childhood progressive low-grade glioma. J Neurooncol. 2010 Oct;100(1):65-71. Epub 2010 Feb 12. link to original article contains verified protocol PubMed

PCV

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PCV: Procarbazine, CCNU (Lomustine), Vincristine

Regimen

Study Evidence
Brandes et al. 2004 Phase II

Chemotherapy

Supportive medications

6-week cycle for up to 6 cycles

References

  1. Brandes AA, Tosoni A, Vastola F, Pasetto LM, Coria B, Danieli D, Iuzzolino P, Gardiman M, Talacchi A, Ermani M. Efficacy and feasibility of standard procarbazine, lomustine, and vincristine chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma recurrent after radiotherapy. A Phase II study. Cancer. 2004 Nov 1;101(9):2079-85. link to original article contains verified protocol PubMed
  2. Triebels VH, Taphoorn MJ, Brandes AA, Menten J, Frenay M, Tosoni A, Kros JM, Stege EB, Enting RH, Allgeier A, van Heuvel I, van den Bent MJ. Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas. Neurology. 2004 Sep 14;63(5):904-6. link to original article PubMed

Temozolomide (Temodar)

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Regimen #1, low dose

Study Evidence
Pouratian et al. 2006 Retrospective

Chemotherapy

Supportive medications

28-day cycle for 12 to 15 cycles

Regimen #2, low dose, longer cycles

Study Evidence
Kesari et al. 2009 Phase II

Chemotherapy

Supportive medications

77-day cycle for up to 6 cycles, progression of disease, or unacceptable toxicity

Regimen #3, traditional initial dosing, then continuous therapy

Study Evidence
Perry et al. 2008 (RESCUE) Phase II

At first recurrence/progression:

Chemotherapy

28-day cycles

Patients with progressive disease are changed to:

Given until progression of disease or unacceptable toxicity

Regimen #4, traditional dosing

Study Evidence
Chinot et al. 2001 Phase II
Nicholson et al. 2007 Non-randomized

Chemotherapy

  • Temozolomide (Temodar) 200 mg/m2 PO once per day on days 1 to 5
    • In Nicholson et al. 2007, patients who previously received craniospinal irradiation (CSI) instead received 180 mg/m2 PO once per day on days 1 to 5

28-day cycle for up to 24 months (in Chinot et al. 2001) or 11 cycles (in Nicholson et al. 2007)

References

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  2. Pouratian N, Gasco J, Sherman JH, Shaffrey ME, Schiff D. Toxicity and efficacy of protracted low dose temozolomide for the treatment of low grade gliomas. J Neurooncol. 2007 May;82(3):281-8. Epub 2006 Nov 3. link to original article contains verified protocol PubMed
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